The present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of formula 1.
Two endothelin receptor subtypes ET.sub.A and ET.sub.B are known so far. The compounds of the present invention possess high affinity to at least one of two receptor subtypes, responsible for the dilation of smooth muscle, such as blood vessels or in the trachea. The endothelin antagonist compounds of the present invention provide a new therapeutic potential, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.
Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 41 1-415 (1988)).
Three endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which resemble one another in structure, exist in the bodies of animals including human, and these peptides have vasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86, 2863-2867 (1989)).
As reported, the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (Japan, J. Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990)).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)), an improved renal function by the endothelin antibody in an acute renal failure model (J. Clin, invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer, 50 (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).
Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A.sub.2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157, 1164-1168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., 13, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184 (1989)). Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res. Commun., 159, 317-323 (1989)). Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276-279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)).
Internal hyperplastic response was induced by rat carotid artery balloon endothelial denudation. Endothelin causes a significant worsening of the internal hyperplasia (J. Cardiovasc. Pharmacol., 22, 355-359 & 371-373(1993)). These data support a role of endothelin in the pathogenesis of vascular restenosis. Recently, it has been reported that both ET.sub.A and ET.sub.B receptors exist in the human prostate and endothelin produces a potent contraction of it. These results suggest the possibility that endothelin is involved in the pathophysiology of benign prostatic hyperplasia (J. Urology, 151, 763-766(1994), Molecular Pharmacol., 45, 306-311(1994)).
On the other hand, endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively. These findings suggest that endothelin is an important mediator for endotoxin-induced diseases (Biochem. Biophys. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
Further, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-inducea renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.
Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)).
It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7), S119-S121 (1991)). One of the endothelin receptors is ET.sub.A receptor Selective to ET-1 rather than ET-3, and the other is ET.sub.B receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348, 730-735 (1990)).
These two subtypes of endothelin receptors are differently distributed in tissues. It is known that the ET.sub.A receptor is present mainly in cardiovascular tissues, whereas the ET.sub.B receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.
Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ET.sub.A receptor but also the ET.sub.B receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.
Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. Further, it is suggested that endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension. Two endothelin receptors ET.sub.A and ET.sub.B are known so far. An antagonistic agent against the ET.sub.B receptor as well as the ET.sub.A receptor is useful as a drug. In the field of anti-endothelin agents, some non-peptidic compounds possessing antagonistic activity against endothelin receptors were already disclosed in patents (for example, EP 0526708 Al, WO 93/08799 Al). Accordingly, it is an object of the present invention to provide a novel therapeutics for the treatment of the above-mentioned various diseases by an invention of a novel and potent non-peptidic antagonist against either ET.sub.A or ET.sub.B receptor.
In order to accomplish the above object, the present inventors have developed an asymmetric conjugate addition which enables them to prepare the compound of Formula I, ##STR1##
a key intermediate in the synthesis of endothelin antagonists of the following structure: ##STR2##
wherein ##STR3## PA1 represents: 5- or 6-membered heterocyclyl, 5- or 6-membered carbocyclyl, and aryl; PA1 R.sup.3b is aryl, or heteroaryl; PA1 R.sup.1 is: C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, or heteroaryl; PA1 R.sup.2 is OR.sup.4 and N(R.sup.5).sub.2 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; and PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl. PA1 wherein ##STR5## PA1 represents: PA1 R.sup.1 is: PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; ##STR6## PA1 R.sup.3a is: PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sup.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2. PA1 1) reacting an .alpha.,.beta.-unsaturated ester or amide ##STR10## PA1 with an organolithium compound, R.sup.1 Li, in the presence of an aprotic solvent at a temperature range of about -78.degree. C. to about 0.degree. C. to give the conjugate adduct, and PA1 2) removing the chiral auxiliary, R.sup.3, with aqueous acid and tetrahydrofuran to give the compound of Formula I. PA1 wherein ##STR12## PA1 represents: PA1 R.sup.1 is: PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; ##STR13## PA1 R.sup.3a is: PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sup.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2. PA1 wherein ##STR15## PA1 represents: PA1 R.sup.1 is: PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; ##STR16## PA1 R.sup.3a is: PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sub.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; PA1 wherein ##STR19## PA1 represents: PA1 R.sup.1 is: PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; ##STR20## PA1 R.sup.3a is: PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sup.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; PA1 1) reacting an .alpha.,.beta.-unsaturated ester or amide ##STR21## PA1 with an organolithium compound, R.sup.1 Li, in the presence of an aprotic solvent at a temperature range of about -78.degree. C. to about 0.degree. C. to give the conjugate adduct; and PA1 2) removing the chiral auxiliary, R.sup.3, with aqueous acid and tetrahydrofuran to give the compound of Formula I. PA1 wherein ##STR26## PA1 represents: PA1 R.sup.1 is: PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; ##STR27## PA1 R.sup.3b is: PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sup.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; PA1 1) reacting a .alpha.,.beta.-unsaturated ester or amide ##STR28## PA1 with an organolithium compound, R.sup.1 Li, in the presence of an aprotic solvent at a temperature range of about -78.degree. C. to about 0.degree. C. to give a conjugate adduct ##STR29## PA1 2) removing the chiral auxiliary with aqueous acid and tetrahydrofuran to give the aldehyde ##STR30## PA1 3) reacting the aldehyde with a Grignard reagent or organolithium reagent formed with R.sup.3b Z, where Z is Br, Cl, or I to form an alcohol ##STR31## PA1 4) oxidizing the alcohol formed with an oxidizing agent to give the ketone ##STR32## PA1 1) reacting a .alpha.,.beta.-unsaturated ester or amide ##STR34## PA1 with an organolithium compound ##STR35## PA1 in the presence of an aprotic solvent at a temperature range of about -78.degree. C. to about 0.degree. C. to give a conjugate adduct ##STR36## PA1 2) removing the chiral auxiliary with aqueous acid and tetrahydrofuran to give the aldehyde ##STR37## PA1 3) reacting the aldehyde with a Grignard reagent or organolithium reagent formed with ##STR38## PA1 to form an alcohol ##STR39## PA1 4) oxidizing the alcohol formed with an oxidizing agent to give a ketone ##STR40## PA1 5) transesterifying the ester with n-butanol and a Lewis acid to give the desired n-butyl ester. PA1 1) a coupling reaction at the one position of Ring A ##STR43## PA1 2) the conversion of the aldehyde (R.sup.3a.dbd.CHO) to the desired chiral auxiliary (R.sup.3), wherein R.sup.3 represents ##STR44## PA1 X and Y are independently: O, S, or NR.sup.5 ; R.sup.4 is C.sub.1 -C.sub.8 alkyl; R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, such that either R.sup.6 and R.sup.7 are not the same and/or R.sup.8 and R.sup.9 are not the same, or R.sup.6 and R.sup.8 or R.sup.7 and R.sup.9 can join to form a 5- or 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2.